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Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)

Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (scleroderma)
Literature review current through: Jan 2024.
This topic last updated: Dec 16, 2022.

INTRODUCTION — The etiology and pathogenesis of the scleroderma disorders are poorly understood. As a result, treatment of these conditions is difficult, incomplete, and not curative. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)" and "Pathogenesis of systemic sclerosis (scleroderma)".)

Patients with diffuse as opposed to limited cutaneous involvement are the most likely to have early and sometimes severe internal organ involvement. These patients are classified as having diffuse cutaneous systemic sclerosis (dcSSc). This is the subset of patients for whom systemic approaches to treatment are most often used.

This topic reviews the systemic approaches to the treatment of systemic sclerosis (SSc, scleroderma). An overview of the treatment of scleroderma disorders and a discussion of the clinical manifestations and diagnosis of SSc are presented separately. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

DIFFICULTIES WITH CLINICAL TRIALS — Clinical trials that evaluate the effectiveness of therapies for systemic sclerosis (SSc) are hampered because of the following problems [1,2]:

The disease is rare with heterogeneous clinical manifestations

There is variable progression within each subset

Organ-based problems require specific therapy

Insensitive outcome measures do not necessarily measure slow increments of change

Assessing global impact in a multicompartment disease is challenging

Clinical diversity and variable natural history make prediction of outcome difficult in placebo-treated patients in randomized trials

Older trials were often based in a single center, had inadequate numbers of enrolled patients, were not suitably controlled (few contained a placebo arm), and discounted heterogeneity, subsets, and staging. Guidelines from the American College of Rheumatology (ACR) committee on design and outcome in clinical trials for disease-modifying drugs address these problems [3].

IMMUNOMODULATION — An activated immune system may be an important stimulus to both fibrotic and vascular lesions in systemic sclerosis (SSc). Its maximum damaging effect may be in the early stages of the disease. Through the production of cytokines and growth factors, for example, initial immune activation could create autocrine loops, which require no further stimulus to perpetuate the fibrotic and vascular lesions (figure 1). These loops could account for the relatively poor response to immune suppression seen in established SSc [4]. Both chlorambucil [5] and fluorouracil (also known as 5-fluorouracil) [6], for example, have failed to slow or reverse skin or internal organ involvement in placebo-controlled trials; in addition, attempts to target the immune system by lymphoplasmapheresis and total lymphoid irradiation have also been without benefit. The latter may even have accelerated worsening of gastrointestinal and pulmonary involvement [7].

A number of immunotherapies are being used in SSc with varying degrees of efficacy. There are no sufficiently defined immunologic targets in SSc against which to design specific compounds, although some emerging possibilities are being developed.

The role of a few of these immunosuppressive agents is discussed in more detail below. We generally discourage the use of glucocorticoids, except in low doses, because they may precipitate renal failure. (See 'Glucocorticoids' below.)

Mycophenolate — Several observational studies have reported promising results with mycophenolate mofetil (MMF) for skin and pulmonary fibrosis [8-13]. One of the largest observational studies, including 326 patients from a number of European centers, that was designed to further explore treatment of diffuse cutaneous systemic sclerosis (dcSSc) with immunosuppressive agents found that MMF was well tolerated and associated with improvement in skin disease over 12 months [13]. There was no evidence of superiority compared with other immunosuppressive agents (methotrexate and cyclophosphamide) that were also used in the cohort.

Results of the SLS-II clinical trial that compared oral cyclophosphamide over 12 months with MMF given over 24 months are supportive of the benefit for lung fibrosis and also suggest benefit for skin in both treatment arms, although the study did not include a placebo-treated arm and so should be interpreted with caution [14,15]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Choice of initial agent'.)

Cyclophosphamide — The role of cyclophosphamide in SSc remains uncertain. Its efficacy as a single agent is unknown. On the other hand, cyclophosphamide in combination with glucocorticoids or plasma exchange is possibly efficacious in some patients [16,17], but controlled studies have not been performed. We primarily use cyclophosphamide in combination with glucocorticoids for patients with fibrosing alveolitis who do not yet have advanced fibrosis. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Initiating therapy'.)

Glucocorticoids — Long-term, high-dose glucocorticoids are potentially toxic and have been implicated in precipitating renal crisis [18]. Any use of such glucocorticoids may increase the risk of this complication [19]. Glucocorticoids should therefore be restricted to patients with myositis, active fibrosing alveolitis, symptomatic serositis, the early edematous phase of the skin disease, refractory arthritis, and tenosynovitis (see "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults"). The lowest possible effective dose should be used in these settings, preferably below 10 mg/day of prednisone.

Cyclosporine — Cyclosporine suppresses cell-mediated immunity and also reduces collagen synthesis. However, the therapeutic potential of cyclosporine in SSc is limited by nephrotoxicity. In one report, for example, three of eight patients developed hypertension and acute renal failure after the onset of cyclosporine therapy; the causal relation to the drug could not be determined [20].

There is preliminary information that suggests that cyclosporine may be helpful in controlling some aspects of SSc [21,22]. One study evaluated 10 patients without hypertension or renal disease [22]. Skin thickening diminished significantly, but there was no change in cardiac or pulmonary disease. Nephrotoxicity was seen at doses above 3 to 4 mg/kg per day. We do not use cyclosporine because its toxicity appears to outweigh any potential clinical benefit.

Controlled observations are clearly needed. It is also possible that other cyclophilins, such as rapamycin, will provide more targeted immunosuppression, improved efficacy, and less toxicity [23].

Other immunosuppressive agents — Other immunosuppressive agents have been used in SSc with varying degrees of efficacy and have been evaluated in trials of varying scientific rigor. By comparison, MTX has been evaluated in randomized, double-blind trials with inconclusive results [24-27]. Although these were not considered to be strongly suggestive of clinical benefit by the investigators, there is some evidence for superiority over placebo, especially with respect to modified Rodnan skin score (mRSS). The European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) recommendations for treatment of SSc have thus offered some support to the use of MTX for skin disease [28].

A small study of rapamycin has been conducted, but it was not powered for efficacy analysis [23]. This may be a strategy warranting further study.

Autologous stem cell transplantation — Studies of autologous hematopoietic stem cell transplantation (HSCT) have demonstrated efficacy in preventing disease progression in SSc patients [29-40]. However, the high incidence of treatment-related mortality (TRM) has limited its use in the management of SSc, and patients should be made to understand the potential risks of this procedure. The major complications associated with HSCT for SSc include treatment-related deaths, malignancies, and infections. The particular challenge is that cardiopulmonary or renal involvement from SSc may make the chemotherapy and fluid load associated with mobilization and conditioning extremely hazardous, and so early TRM is a particular risk. Careful assessment pre-HSCT is essential to minimize TRM.

Based upon emerging trial data and our own experience, HSCT may be most beneficial in selected patients with early, severe dcSSc. These patients may have moderate (but not severe) internal organ involvement and progressive disease despite an initial trial of immunosuppression. However, such patients should be referred for further evaluation to specialized centers with expertise performing HSCT for SSc. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Hematopoietic stem cell transplantation'.)

In a randomized trial (Scleroderma: Cyclophosphamide or Transplantation [SCOT]) including 75 patients with severe SSc of five years' or less duration and pulmonary or renal involvement, patients were assigned to receive either myeloablative autologous HSCT or 12 monthly cyclophosphamide infusions [40]. The primary endpoint was a global rank composite score that compared each individual patient with all other patients on the basis of a hierarchy of disease features assessed at 54 months, with rankings from highest to lowest for death, event-free survival, forced vital capacity, scores on the Health Assessment Questionnaire Disability Index, and Rodnan skin score. In the intention-to-treat analysis, global rank composite scores favored transplantation over cyclophosphamide (67 percent of 1404 pairwise comparisons favored transplantation and 33 percent favored cyclophosphamide). Secondary per-protocol analyses of the global rank composite scores and traditional endpoints (ie, overall survival, event-free survival, modified Rodnan skin score, and disease-modifying antirheumatic drug [DMARD] use) were consistent with the primary outcome, favoring transplantation. The transplant-related mortality was 3 percent at 54 months and 6 percent at 72 months, which is less than that reported in previous studies. However, this difference in mortality from previous trials may reflect differences in baseline patient factors, such as the exclusion of patients with heart involvement or pulmonary arterial hypertension.

The Autologous Stem cell Transplantation International Scleroderma (ASTIS) trial, which used a nonmyeloablative transplantation, is the largest multicenter study of the safety and efficacy of treatment with autologous HSCT compared with conventional cyclophosphamide therapy in patients with early dcSSc [41]. A total of 156 dcSSc patients were randomly assigned to receive either HSCT (n = 79) or 12 monthly pulses of intravenous cyclophosphamide (n = 77). The primary endpoint was event-free survival, which was defined as the time until death due to any cause or the development of persistent major organ failure (eg, heart, lung, or kidney). Secondary endpoints included TRM, toxicity, changes in skin thickening, organ function, and quality of life. HSCT resulted in worse early, but better long-term, event-free and overall survival:

During the first year, the number of events was higher in the HSCT group (13 versus 8 events). Most of these events in the HSCT group occurred during the first three to six months after transplant, and most were treatment-related (8 of 13). However, between the first and fourth years of follow-up, an additional two events occurred in the HSCT group compared with an additional 12 events in the cyclophosphamide group.

Since the increased number of events in the HSCT group occurred within the first six months, the event-free survival actually favors HSCT at two years (hazard ratio 0.35, 95% CI 0.16-0.74) and at four years (hazard ratio 0.34, 95% CI 0.16-0.74).

Consistent with previous studies [29,31,34,35], the ASTIS trial also found that HSCT was associated with significant improvements in lung function, skin softness, functional ability, and quality of life. However, HSCT produced a higher incidence of viral infections and a significant decrease in creatinine clearance. Finally, seven of the eight patients who died from HSCT-related causes were current or former smokers.

Patient selection is thought to be a critical factor in determining successful outcomes of HSCT. Specifically, TRM and lack of improvement of diffusion capacity may partly reflect the selection of patients with more severe cardiorespiratory disease that may not always be apparent on pre-HSCT evaluation. A retrospective analysis of 90 patients with SSc who underwent HSCT on a compassionate basis suggested that cardiac screening guidelines for HSCT for SSc should be more extensive, including right heart catheterization, a fluid challenge test, and cardiac magnetic resonance imaging (MRI) in addition to echocardiography [35]. Improvement in diffusion capacity was observed in patients with normal baseline cardiac function and electrocardiographic findings. In addition, the results of the ASTIS trial described above also suggest that the smoking status of patients may impact outcomes of HSCT [41].

These findings support the need for early referral of patients for HSCT, before cardiac dysfunction occurs, along with screening guidelines for patients with SSc under evaluation for HSCT [35,42,43]. SSc patients should undergo standard screening for internal organ involvement as well as cardiopulmonary evaluations combining pulmonary function tests, echocardiography, cardiac MRI, and invasive hemodynamic studies if clinically indicated. In general, patients are selected based upon criteria used for enrollment in clinical trials that demonstrate a therapeutic benefit of HSCT [34,41]. As noted earlier, patients considered for HSCT should be referred to specialized centers with expertise in the procedure for further evaluation and treatment. Our approach to the pre-transplant cardiopulmonary evaluation for SSc patients is consistent with guidelines published by the European Society for Blood and Marrow Transplantation [43].

Appropriate case selection remains challenging because those patients with more severe organ-based disease are generally excluded from trial protocols despite poor outcome with standard immunosuppression. Future trial protocols will assess benefit of HSCT as first-line therapy [44].

ANTIFIBROTIC DRUGS — The treatment of established fibrosis is a very difficult therapeutic problem, since there is no safe and effective method of removing excess insoluble cross-linked collagen fibers without damaging the structural framework of the body and individual organs. Fibrotic lesions may occur with frightening speed in patients with systemic sclerosis (SSc). This fact, alone, would justify starting an antifibrotic drug as soon as possible in patients with diffuse disease and possibly administering such a drug concurrently with an immunosuppressive agent.

The major problems with the available antifibrotic drugs are that they are slow to act and are often not powerful enough to prevent rampant fibrosis. As a result, escalation of the drug dose in the proper setting should be as rapid as possible.

Antifibrotic drugs are not necessary for cutaneous manifestations in patients with limited cutaneous SSc (lcSSc), but a careful watch should be kept for significant visceral fibrosis among such patients. The use of the ever-improving "antibody-based" risk stratification for internal organ involvement may permit the early identification and appropriate treatment of lung fibrosis (table 1).

D-penicillamine — D-penicillamine is a drug capable of affecting both collagen biosynthesis and the immune system. One possible mechanism is that autoantibodies in SSc are formed against autoantigens that have been fragmented via reactive oxygen species and specific metals, such as copper or iron [45]. Penicillamine, a chelator of metals, may therefore minimize the formation of these autoantigens. (See "Pathogenesis of systemic sclerosis (scleroderma)", section on 'Autoantibodies'.)

The precise role of penicillamine in the treatment of SSc has not been determined. Estimates of the efficacy of penicillamine and the effect upon survival can be found in uncontrolled studies published by several groups with extensive experience with this drug. The possible benefit of penicillamine can be illustrated by the following observations:

A retrospective analysis from Pittsburgh compared 73 patients with SSc who had received penicillamine with 45 patients who had not [46]. The mean daily dose of penicillamine varied from 500 to 1500 mg, and therapy was given for a mean period of 24 months. The mean follow-up was at least three years. Patients treated with penicillamine showed an improved cumulative five-year survival (80 percent) and a lower rate of new visceral involvement compared with patients not exposed to penicillamine. Except for skin softening, other intergroup differences did not reach statistical significance [46].

Another group reported their 15-year, uncontrolled experience with penicillamine in SSc [47]. This study consisted of 69 selected patients with diffuse disease of less than 18 months' duration in whom a 30 percent increase in skin involvement had occurred in the preceding six months. Treatment with penicillamine (750 mg/day) for at least six months was associated with a 75 percent improvement in skin sclerosis (from 65 to 16 percent of total body surface) and with an 80 percent five-year cumulative survival rate. Renal disease was uncommon, and pulmonary disease was not progressive in patients treated for more than six months.

These and other studies have noted that skin sclerosis worsened during the first four to six months despite therapy. This observation emphasizes the necessity for the development of a rapidly acting antifibrotic agent.

To assess the effects of high-dose penicillamine on disease activity, 134 patients with early diffuse cutaneous SSc (dcSSc) were enrolled in a multicenter double-blind randomized study comparing high-dose (750 to 1000 mg/day) with low-dose (125 mg every other day) therapy [48]. Sixty-eight patients completed 24 months of therapy. No significant differences were observed between the two treatment groups with respect to the skin thickness scores and the incidence of renal crisis and mortality. However, 16 of the 20 adverse event-related withdrawals occurred in the high-dose treatment group. Although this study could not answer the question of whether low-dose penicillamine is effective, there appeared to be no advantage in using high-dose penicillamine. Based upon the results of this key trial, we do not initiate penicillamine therapy for SSc. However patients who are stable on therapy may be continued, with dose reduction toward the low dose used in the controlled trial (125 mg every other day).

Interferons — The interferons have been reported to be beneficial in the therapy of various diseases, including SSc. In particular, an antifibrotic effect has been reported in vitro. However, subsequent data have implicated interferons in the pathogenesis of some autoimmune diseases. Interferon (IFN)-gamma is a more potent inhibitor of collagen synthesis in vitro than IFN-alpha. It has other effects, however, which may contribute to aberrant cellular activation in SSc (see "Pathogenesis of systemic sclerosis (scleroderma)"). As examples, in vitro IFN-gamma can lead to:

Macrophage activation

Class II antigen expression (DR, DP, DQ) on endothelial and fibroblast cells

Increased interleukin (IL) 2 receptor expression

Increased intracellular adhesion molecule-1 expression on endothelial cells

Immunoglobulin G (IgG) Fc receptor expression

These concerns have been apparently confirmed in uncontrolled studies in which IFN-gamma was associated with considerable vascular side effects, including renal hypertensive crisis [49]. As a result, no controlled studies are planned, and the studies that have been performed provide evidence that in some cases IFN may be a driver of pathology in SSc.

IFN-alpha has received less attention than IFN-gamma. A pilot study of 14 patients with early diffuse disease of less than three years' duration found a significant measurable reduction in type I collagen synthesis by fibroblasts cultured from uninvolved skin and found stabilization or improvement in the skin test in 10 of the patients [50].

However, a multicenter double-blind study of 35 patients found that IFN-alpha provides no increased benefit compared with placebo and may be deleterious [51]. In this report, patients with early SSc were randomized to IFN-alpha (13.5 million units per week given subcutaneously for 12 months) or placebo. Compared with the placebo group, intent-to-treat analysis found that the group treated with IFN-alpha had more substantial skin involvement (as assessed by the skin score) and had a significantly greater deterioration in lung function (as assessed by the forced vital capacity [p = 0.01] or by the diffusing capacity for carbon monoxide [p = 0.002]).

Iloprost — In addition to vasodilating effects, iloprost may also have antifibrotic properties. Among six patients with dcSSc, five days of iloprost infusion decreased the dermal interstitial fluid concentration of the profibrotic cytokine, connective tissue growth factor [52]. However, objective evidence of a clinically important antifibrotic effect has not been established. Iloprost is not available in the United States, but both oral and intravenous preparations are available in some other countries. It has not been determined whether its effects are shared with other prostacyclin analogues, such as epoprostenol.

Relaxin — A natural antifibrotic protein, relaxin, is produced during pregnancy by the uterus and the corpus luteum. It promotes the degradation of collagen and antagonizes the production of new collagen by fibroblasts. Despite encouraging trends in a small controlled trial, a subsequent larger multicenter trial did not find any benefit from relaxin, and withdrawal of relaxin was associated with serious renal adverse events [53,54]. Further commercial development of this agent for treatment of SSc is not being considered.

Anti-TGF-beta — The first trial of anti-transforming growth factor beta (TGF-beta) in SSc was negative. Metelimumab, a monospecific antibody targeting TGF-beta1 was found to be of low affinity, and the trial did not demonstrate benefit for skin fibrosis. A more potent anti-TGF-beta-specific antibody targeting all the TGF-beta isoforms, fresolimumab, was tested in an open-label study with clinical improvement and consistent data from molecular markers in skin biopsies [55]. This provides a platform for possible future treatment strategies in SSc that target TGF-beta ligands. The universal importance of TGF-beta in fibrosis and availability of therapeutics targeting this ligand and related signaling pathways makes this a compelling strategy. However, until this is shown to be both safe and effective, it remains very much in the research arena.

Anticytokine therapy — Better understanding of likely key mediators in pathogenesis has raised the possibility of targeted therapy. As discussed above, there is already evidence that conventional treatments such as parenteral prostacyclin suppress key profibrotic factors, such as connective tissue growth factor (CTGF). Endothelin antagonism may also attenuate TGF-beta signaling [56]. Anti-tumor necrosis factor (TNF)-alpha agents, while theoretically attractive, have not proven to be beneficial in clinical trials [57,58].

When recombinant anti-TGF-beta1 (investigational agent CAT-192) was assessed in a small pilot study, no adverse effects were noted, but neither was there any suggestion of efficacy [59]. This result suggests that blockade of more than one isoform of TGF-beta may be necessary.

The use of combinations of anticytokine therapies (eg, the use of agents directed against both TGF beta and CTGF) is being explored [60]. In addition, it is possible that the vasoconstrictor peptide endothelin may have a specific role in fibrosis, and potentially broader use outside the complication of pulmonary arterial hypertension is being explored.

Tocilizumab — Although IL-6 was originally characterized as a proinflammatory mediator with potent effects on the adaptive immune system, it is emerging as a potent mediator that is produced by a large number of cell types in response to damage or activation. Tocilizumab, a humanized anti-human IL-6 receptor antibody, has been shown to have potent antifibrotic activity in vitro, and this may result from its ability to signal through many cell types via the glycoprotein (gp) 130 trans-signaling system. Data from clinical trials have suggested a potential antifibrotic effect of blocking IL-6 signaling using tocilizumab [61-63]. In one trial, there was trend of benefit for skin fibrosis and lung function [63]. The focuSSced trial replicated these results, again only showing a trend of benefit overall for skin in a population with milder disease, but with a statistically significant reduction in the progression of skin fibrosis and robust impact on lung function and on HRCT-confirmed lung fibrosis (NCT02453256). This impact appears to be greatest in those cases with early-stage active skin disease and markers of increased acute phase response that are associated with elevated levels of serum IL-6. One small case series indicates that discontinuation of tocilizumab may be associated with disease recrudescence [64]. On the basis of its impact on lung function and HRCT severity in the phase 3 focuSSced trial, tocilizumab is now approved by the US Food and Drug Administration (FDA) as treatment to slow progression of lung fibrosis in SSc [65,66]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)".)

Nintedanib — Nintedanib, a tyrosine kinase inhibitor in routine use for treatment of idiopathic lung fibrosis (IPF), is now approved for use in patients with SSc-associated interstitial lung disease (ILD) [67] and progressive ILD in connective tissue disease [68]. The role of this drug in the treatment of ILD for patients with SSc is discussed in detail separately. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Nintedanib'.)

Pirfenidone — Pirfenidone is also in routine use as an antifibrotic agent in IPF, although the mechanism of action is less clear than for nintedanib. It has not yet been formally tested in a large trial of SSc-associated ILD, but a small open-label safety study demonstrated that it was well tolerated in SSc [69]. An ongoing trial aims to address the potential value of adding pirfenidone on top of mycophenolate mofetil (MMF) in a large cohort of SSc-ILD cases (NCT03221257).

Immunosuppression as an indirect antifibrotic approach: MMF, cyclophosphamide, HSCT — The distinction between antifibrotic and immunomodulatory treatment for SSc is increasingly challenged by data emerging from clinical trials and observational cohorts that demonstrate improvement or slowing in progression of fibrosis in skin or lung after treatment strategies that are primarily immunosuppressive or antiinflammatory. This is also supported by data from preclinical and translational studies. Thus, cyclophosphamide and MMF have both been associated with trends of improvement in skin and lung based on analysis of trial cohorts [13,14,70]. Most persuasive are the data from trials of autologous hematopoietic stem cell transplantation (HSCT), where there is clear evidence of reversal of skin fibrosis assessed by modified Rodnan skin scores (mRSS) and lung fibrosis assessed by lung function testing and quantitative high-resolution computed tomography (HRCT) analysis (see 'Autologous stem cell transplantation' above). Similarly, results from a trial of tocilizumab, a humanized anti-human IL-6 receptor antibody, have suggested potential benefit on lung fibrosis. (See 'Tocilizumab' above.)

INVESTIGATIONAL APPROACHES — There is an urgent need to improve our repertoire of antifibrotic agents and develop novel therapeutic approaches to systemic sclerosis (SSc). A growing understanding of the cellular and molecular events that lead to fibrosis and improvements in technology provide a favorable basis for the development of effective agents. Potentially promising approaches for the treatment of SSc include the following:

Imatinib — Imatinib mesylate, a protein tyrosine kinase inhibitor, is highly effective for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors, and limited data suggest possible benefit in patients with SSc. The selective inhibition of tyrosine kinase interferes with the signaling of both platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta, two pivotal mediators of the fibrotic process in SSc [71].

An open-label prospective study of imatinib (400 mg/day) in 30 patients with diffuse cutaneous SSc (dcSSc), but without controls, showed improvement in modified Rodnan skin scores (mRSS) and in forced vital capacity compared with baseline after 12 months [72]. Mild to moderate adverse effects were common, including edema requiring treatment with diuretics. The most common causes of dose adjustment or interruption in therapy were musculoskeletal complaints, fluid-related issues, intercurrent illnesses, gastrointestinal complaints, and constitutional symptoms (37, 27, 23, 23, and 20 percent, respectively). Randomized trials will be required to distinguish possible benefit from imatinib from natural history of disease or from effects of other interventions.

The theoretical basis supporting use of imatinib includes findings of an in vitro study of fibroblasts from SSc patients, in which cells isolated and cultured from lesional skin were stimulated with TGF-beta and PDGF and were then exposed to imatinib [73]. This led to the inhibition of extracellular matrix protein production in a dose-dependent manner. In a separate study, imatinib blocked, in vitro, the Smad1/CCN2 pathway, which is also implicated in the development of fibrosis [74]. Furthermore, four case reports suggest that imatinib may reduce fibrosis in several clinical settings [75-78].

Other protein tyrosine kinase inhibitors are also being studied for possible antifibrotic effects. These include dasatinib and nilotinib [79]. In addition, the two licensed drugs for idiopathic lung fibrosis, nintedanib and pirfenidone, have been suggested as potentially useful agents for lung or skin fibrosis in SSc, but formal clinical trial data are needed to assess this [80]. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Investigational approaches'.)

Rituximab — There is a growing evidence base supporting use of rituximab as a B-cell-depleting agent in SSc. Data from case series and small clinical trials have been generally positive, and a retrospective cohort analysis from the large European Scleroderma Trials and Research group (EUSTAR) cohort also suggested benefit compared with standard immunosuppression. However, the precise mechanism of benefit is less clear, and it may be that a subset of patients is driving the overall treatment response. B-cell infiltration has been demonstrated within skin and lung biopsies of SSc patients, and limited data have suggested improvement in skin and lung disease with B-cell depletion [81-91]. One of the larger studies to assess the effects of rituximab on skin and lung fibrosis included 63 SSc patients treated with rituximab compared with 25 matched controls [90]. After a follow-up period of approximately seven months, patients treated with a single course of rituximab demonstrated a significant improvement in the mRss. Among SSc patients with interstitial lung disease (ILD), rituximab also prevented a further decline in forced vital capacity compared with matched controls. There were no serious adverse events among rituximab-treated patients. An open-label randomized trial including 60 patients assigned to receive either rituximab or cyclophosphamide found that patients receiving rituximab demonstrated greater improvements in the percent-predicted forced vital capacity as well as the mRSS compared with the cyclophosphamide group [92]. However, additional studies are needed to establish the long-term efficacy and safety of rituximab for skin and lung fibrosis in SSc before routine use can be recommended. A small trial in Japan reported benefit of rituximab compared with placebo for improving skin score in SSc and also demonstrated benefit for lung function [93]. The drug is now approved for treatment of SSc in Japan. The role of rituximab in the treatment of patients with ILD in SSc is discussed in detail separately. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Rituximab'.)

Intravenous immunoglobulin — There are case series and small trials suggesting potential benefit from intravenous immunoglobulin for skin fibrosis as well as other symptoms, including gastrointestinal tract manifestations, of SSc. Clinical trials are being planned, but the mechanism of action for antifibrotic activity remains unclear. Several small, uncontrolled studies have evaluated the effect of intravenous administration of immune globulin on dermal fibrosis, each with reported improvement [79,94]. The largest series to evaluate the effect of IVIG on active cutaneous disease included 30 patients with refractory dcSSc, the majority of whom were on concomitant immunosuppressive therapy [94]. A significant improvement in skin thickening was detected at 12 months compared with historical controls from negative clinical trials. In addition, a group of patients treated with IVIG demonstrated an improvement in the mRSS that was similar to a group of patients treated with mycophenolate mofetil (MMF).

Epigenetic effects — Epigenetic changes, which are stable phenotypic changes that persist in a heritable manner but which are not the result of changes in deoxyribonucleic acid (DNA) sequence, may play a role in the profibrotic myofibroblasts of patients with SSc. Agents that interfere with deacetylation of histone proteins may limit the ability of transformed cells to proliferate. The protein deacetylase enzyme inhibitor trichostatin A is being assessed for possible antifibrotic effects [79]. (See "Pathogenesis of systemic sclerosis (scleroderma)", section on 'Fibroblast activity and collagen synthesis' and "Genetics: Glossary of terms", section on 'Epigenetic change' and "Principles of epigenetics", section on 'Therapeutic uses'.)

Immune tolerance induction — Another possible approach to the treatment of SSc is the induction of T-cell tolerance by the administration of oral bovine type I collagen. This approach was evaluated in a randomized, placebo-controlled trial in which 168 patients were assigned to 12 months of therapy with oral bovine type I collagen (160 mg daily) or placebo [95]. The primary outcome, change in the mRSS, was not different from placebo-treated patients at 12 or 15 months of follow-up in the total population of treated patients. However, in a secondary subgroup analysis, treated patients with late-phase disease (more than 3 to 10 years) had a significant reduction in mRSS. Further studies are required.

Other agents

Riociguat – A trial of riociguat was performed in very early-stage cases of diffuse SSc to explore potential for prevention of worsening of skin fibrosis [96]. Despite strong preclinical support and trend of benefit, the study was considered negative, and this approach to treatment of skin fibrosis is not being pursued for fibrosis, although benefit for vasculopathy has been observed.

Endothelin antagonist – There is no evidence to support an antifibrotic effect of endothelin receptor antagonists such as bosentan, despite benefit for reduction in number of new digital ulcers in SSc and use for pulmonary arterial hypertension. The Bosentan Use in Interstitial Lung Disease (BUILD)-2 trial was a robust study that failed to demonstrate any benefit for lung fibrosis in SSc-ILD and a parallel study in idiopathic lung fibrosis (IPF; BUILD-1) was also negative [97].

Lanifibranor – There are strong preclinical data supporting a potential antifibrotic role for the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma [98]. This led to a completed phase 2 clinical trial exploring potential benefit of lanifibranor, a pan-PPAR agonist, for skin fibrosis in dcSSc. The data have not yet been fully reported, but the primary endpoint was not met, and there is no evidence that this approach to treating skin or other aspects of SSc is beneficial. This illustrates the challenges of extrapolating from strong preclinical results to identify potential benefit in human disease.

Lenabasum – Lenabasum is a synthetic endocannabinoid that selectively activates the CB2 receptor that is expressed on many cell types, including fibroblasts and immune cells. Mechanistic data suggest an antifibrotic and immunomodulatory effect, which promotes resolution of injury responses and which may be helpful in a number of chronic diseases characterized by scarring in response to tissue damage, including SSc. A small phase 2 trial over 16 weeks with open-label extension supported benefit, but a large phase 3 trial was negative overall in SSc and so clinical development is not continuing [99].

Romilkimab – Targeting cytokines that may link immune-inflammation and fibrosis is an attractive strategy, and this has led to present evaluation of romilkimab, a bispecific antibody that binds to IL-4 and IL-13. This trial will soon report the primary data and, if positive, may provide an additional investigational approach to treatment for skin or lung fibrosis in SSc. No results from the study are yet available.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS — Immunomodulatory and antifibrotic approaches to the treatment of systemic sclerosis (SSc), while theoretically appealing, have not been shown to be more beneficial than harmful. While recognizing the limited data available to guide therapy, we recommend the following agents in certain circumstances:

The combination of glucocorticoids and cyclophosphamide may be used in patients with severe or progressive lung fibrosis in SSc who have yet to develop advanced fibrotic lung disease. (See "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Initiating therapy'.)

Glucocorticoids, preferably in doses of less than the equivalent of prednisone 10 mg/day, may be used for myositis, symptomatic serositis, arthritis, or tenosynovitis that is refractory to use of nonsteroidal antiinflammatory drugs (NSAIDs). (See 'Cyclophosphamide' above and 'Glucocorticoids' above.)

Emerging data suggest that high-intensity immunosuppression may benefit skin and function in diffuse cutaneous SSc (dcSSc), but high-dose cyclophosphamide with autologous stem cell rescue may be associated with significant treatment-related mortality (TRM). Thus, case selection to target patients in whom the risk-to-benefit ratio is most favorable is critical. (See 'Autologous stem cell transplantation' above.)

Several case reports and one phase 3 trial suggest improvement in skin and lung disease with B-cell depletion. However, additional studies are needed to establish the long-term efficacy and safety of rituximab in SSc patients before routine use can be recommended. (See 'Rituximab' above.)

There is an urgent need to improve our repertoire of antifibrotic agents and develop novel therapeutic approaches to SSc. A growing understanding of the cellular and molecular events that lead to fibrosis and improvements in technology provide a favorable basis for the development of effective agents. (See 'Investigational approaches' above.)

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Topic 7549 Version 39.0

References

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